Smoking is the major risk factor, which causes 90% of lung cancer. However, only 1 in 10 smokers develop the disease, and a better definition of the genetic susceptibility factors is needed. This study evaluates whether estrogenic signaling is associated with greater lung susceptibility I for some smokers. Recently, estrogen receptor beta (ERb) was discovered to be expressed in human lung tissue and possibly absent in cancerous tissue. Although little is known about the function of estrogen receptors in lung pathology and physiology, we know that ERb negatively regulates cell growth in the prostrate and possibly other tissues. We also know that smoking as anti-estrogenic effects and could decrease expression of ERb in the lung tissue by several mechanisms including activation of proteasome-dependent degradation, promoter methylation, and activation of the aryl hydrocarbon receptor pathway. In addition, it is known that smoking-induced silencing of p16 and other genes is an early event in lung carcinogenesis. We propose to examine expression-changes of the estrogen receptors alpha and beta, and induction of CYP1A1 and CYP1B1 by smoking in 87 human lung autopsy tissues as a possible early event in the lung carcinogenesis pathway. Smoking status of the autopsy donors (42 males and 45 females) was determined in our laboratory by quantification of serum cotinine and eleven polycyclic aromatic hydrocarbons in the lung tissue. We propose to analyze localization of the ER and CYP isoforms in the lung tissue by immunohistochemistry and quantify expression of the proteins by western blot and ELISA. The goal of the study is to improve our understanding of lung cancer etiology and susceptibility. The study is novel as it begins to investigate the emerging field of estrogenic signaling in lung cancer and in particular effects of smoking on this pathway in normal human lung tissue. This research is needed to optimization cancer prevention strategies and therapeutic interventions. The grant would provide critical support for this pilot study, whose results will lead to refined hypotheses testable in future research.